Many neurodegenerative diseases, including spinal and bulbar muscular atrophy (SBMA) and ALS, result from protein misfolding and accumulation due to a variety of both genetic and environmental causes. SBMA is an adult-onset neuromuscular disease that is caused by polyglutamine expansion within the androgen receptor (AR);it is related mechanistically to other neurodegenerative diseases caused by polyglutamine expansion. Although the precise pathway leading to neuronal dysfunction and death is unknown, the evaluation of transgenic mouse and cell models of these diseases has yielded many mechanistic clues. Our transgenic cell and mouse models of SBMA reproduce the proximate events of polyglutamine-dependent proteolysis and nuclear aggregation, making these models highly useful for the analysis of the mechanistic basis for these upstream events. SBMA stands apart from other polyglutamine diseases in that its onset and progression are androgen- dependent. Our preliminary studies in cell models of SBMA indicate that a structural change in the AR that occurs upon androgen binding and that involves an interdomain interaction between the amino- (N-) and carboxyl- (C-) terminal regions is required for mutant AR aggregation and toxicity. Our long- term objectives are to use our transgenic mouse and cell models to determine the role of the N/C interaction in vivo and to develop a mechanistic understanding for this role. We predict that these studies will reveal further details about the step or steps in AR trafficking and metabolism that are derailed by the polyglutamine expansion. To reach these goals, we propose three specific aims: 1) To evaluate the effect of polyglutamine expansion on the AR N/C interaction, using both imaging and biochemical approaches;2) To determine the role of the AR N/C interaction in a mouse model of SBMA;3) To determine the mechanistic basis by which the N/C interaction impacts polyglutamine- expanded AR metabolism. We anticipate that results from these studies will lead us to a new understanding of the molecular pathogenesis of SBMA and enhance our development of new therapies for SBMA. PUBLIC HEALTH RELEVANCE: Spinal and bulbar muscular atrophy (SBMA) is one of 9 polyglutamine diseases, which are themselves part of a large family of neurodegenerative diseases characterized by protein misfolding and accumulation;these diseases also include Alzheimer's disease, Huntington's disease, Parkinson's disease and amyotrophic lateral sclerosis (ALS). We have identified a novel target in SBMA that involves the interdomain (N/C) interaction of the mutant androgen receptor protein. The studies proposed here will determine both the role and the mechanistic basis for this modification in SBMA, and in so doing, will open new and powerful opportunities for therapeutic development.